Asymmetric hydrogenation of acyl enamides

Abstract

The present invention relates to the asymmetric hydrogenation of acyl enamides for preparing carbamoyl acylamide indan derivatives, which are useful intermediates for the preparation of compounds used in the treatment of various CNS disorders.

1 . A method of preparing a carbamoyl acylamide indan compound of formula I  
     
       
         
         
             
             
         
       
     
     comprising the steps of, 
 a) providing an acyl enamide of formula II, and  
                     
 b) hydrogenating the acyl enamide of formula II in the presence of a catalyst to form the enantiomeric compound of formula I, wherein R is a carbamoyl represented by R 1 R 2 NCOO—, wherein R 1  and R 2  are each independently selected from hydrogen, a straight or branched chain C 1 -C 6  alkyl group or a benzyl group.  
 
   
   
       2 . The method of  claim 1 , wherein R 1  is methyl.  
   
   
       3 . The method of  claim 1 , wherein R 2  is ethyl.  
   
   
       4 . The method of  claim 1 , wherein R 1  is methyl and R 2  is ethyl.  
   
   
       5 . The method of  claim 1 , wherein the catalyst is an asymmetric transition metal catalyst.  
   
   
       6 . The method of  claim 5 , wherein the transition metal M of the catalyst is selected from the group consisting of ruthenium (Ru), rhodium (Rh) and iridium (Ir).  
   
   
       7 . The method of  claim 6 , wherein the transition metal M of the catalyst is rhodium.  
   
   
       8 . The method of  claim 5 , wherein the asymmetric transition metal catalyst is in the form of a homogeneous chiral ligand transition metal precatalyst of the formula [L−M X]Y, wherein L is a chiral ligand, M is a transition metal, X is an organic moiety and Y is an anion.  
   
   
       9 . The method of  claim 8 , wherein the anion Y is selected from the groups consisting of ClO 4   − , BF 4   − , PF 6   − , and SbF 6   − .  
   
   
       10 . The method of  claim 9 , wherein the anion Y is BF 4   − .  
   
   
       11 . The method of  claim 8 , wherein the organic moiety X is an arene group having from 6 to 20 carbon atoms or an unsaturated cyclic or acyclic organic group, selected from the group consisting of olefin, diene and cyano.  
   
   
       12 . The method of  claim 11 , wherein the organic moiety is a diene selected from the group consisting of 1,3-butadiene, 2,5-norbornadiene, 1,5-cyclooctadiene (COD) and cyclopentadiene.  
   
   
       13 . The method of  claim 12 , wherein the organic moiety is cyclooctadiene (COD).  
   
   
       14 . The method of  claim 8 , wherein the chiral ligand L is selected from the group consisting of chiral diphosphine derivatives, chiral atropoisomeric diphosphine derivatives, chiral monodentate phosphoramidine derivatives, chiral biphospholane derivatives, chiral FerroTANE derivatives and chiral ferrocenyl phosphine derivatives.  
   
   
       15 . The method of  claim 14 , wherein the chiral ligand L is selected from the group consisting of (R,R)-Me-DuPhos, (R,R)-Et-DuPhos, (R,R)-Me-BPE, (R,R)-Et-BPE, and (S,S)—Ph-BPE.  
   
   
       16 . The method of  claim 1 , wherein the catalyst is activated in situ using a precatalyst selected from the group consisting of [(R,R)-Me-DuPhos Rh COD]BF 4 , [(R,R)-Et-DuPhos Rh COD]BF 4 , [(R,R)-Me-BPE Rh COD]BF 4 , [(R,R)-Et-BPE Rh COD]BF 4 , and [(S,S)—Ph-BPE Rh COD]BF 4 .  
   
   
       17 . The method of  claim 1 , wherein the hydrogenation is carried out in an organic solvent selected from the group consisting of an ether, an aromatic hydrocarbon, a halogenated hydrocarbon, and an alcohol.  
   
   
       18 . The method of  claim 17 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran, tetrahydropyran, diethylether, benzene, toluene, dichloromethane, methanol, ethanol and isopropanol.  
   
   
       19 . The method of  claim 18 , wherein the organic solvent is methanol.  
   
   
       20 . The method of  claim 1 , wherein the hydrogenation is carried out with the acyl enamide substrate present in the reaction mixture in an amount in excess to the amount of the catalyst, the molar ratio of the carbamoyl acyl enamide of formula (II) to the optically active chiral ligand transition metal catalyst in the range from 50/1 to 10000/1.  
   
   
       21 . The method of  claim 20 , wherein the molar ratio is from 100/1 to 5000/1.  
   
   
       22 . The method of  claim 21 , wherein the molar ratio is from 1000/1 to 5000/1.  
   
   
       23 . The method of  claim 1 , wherein the hydrogenation is carried out under a hydrogen pressure from about 0.5 to about 20 bar.  
   
   
       24 . The method of  claim 23 , wherein the hydrogen pressure is from about 1 to about 10 bar.  
   
   
       25 . The method of  claim 24 , wherein the hydrogen pressure is from about 4 to about 10 bar.  
   
   
       26 . The method of  claim 1 , wherein the hydrogenation is carried out at a temperature from about −20° C. to about 100° C. for a period of time of about 10 minutes to about three days.  
   
   
       27 . The method of  claim 26 , wherein the temperature is from about 20° C. to about 100° C.  
   
   
       28 . The method of  claim 27 , wherein the temperature is from about 40° C. to about 60° C.  
   
   
       29 . The method of  claim 26 , wherein the period of time is from about 1 hour to about 1 day.  
   
   
       30 . The method of  claim 29 , wherein the time period is from about 4 hours to about 1 day.  
   
   
       31 . The method of  claim 1 , wherein the acyl enamide of formula II is prepared by a process comprising the steps of, 
 a) reacting 6-hydroxy indanone with a carbamoylhalogenide of formula III                          wherein X is a halogen, in a reaction mixture to form a carbamoyl indanone of formula IV,                          b) reacting the carbamoyl indanone of formula IV with a hydroxylamine in the presence of a base to form a carbamoyl oxime of formula V, and                          c) reducing the carbamoyl oxime of formula V to form the carbamoyl acyl enamide of formula II, wherein R 1  and R 2  are each independently a hydrogen, a straight or branched alkyl group or a benzyl group.    
   
   
       32 . The method of  claim 31 , wherein the reduction of the carbamoyl oxime of formula V is with metal in the presence of acetic anhydride in an organic solvent.  
   
   
       33 . The method of  claim 32 , wherein the metal is selected from the group consisting of Fe and Ru.  
   
   
       34 . The method of  claim 33 , wherein the organic solvent is dimethylformamide.  
   
   
       35 . The method of  claim 31 , wherein to the reaction mixture of step a) a base is added.  
   
   
       36 . The method of  claim 35 , wherein the base is an alkalimetal carbonate.  
   
   
       38 . The method of claim  37 , wherein the alkalimetal carbonate is potassium carbonate.  
   
   
       38 . The method of  claim 31 , wherein the carbamoylhalogenide of formula III is carbamoylchloride.  
   
   
       39 . The method of  claim 31 , wherein R 1  is methyl and R 2  is ethyl in the carbamoylhalogenide of formula III.  
   
   
       40 . The method of  claim 31 , wherein the base in step b) is an alkali acetate.  
   
   
       41 . The method of  claim 40 , wherein the alkali acetate is sodium acetate.  
   
   
       42 . The method of  claim 31 , wherein step b) is carried out in a reaction mixture with an organic solvent.  
   
   
       43 . The method of  claim 42 , wherein the organic solvent is methanol.  
   
   
       44 . The method of  claim 42 , wherein the reaction mixture is a 1:1 molar suspension of the combination of hydroxylamine and a base and the organic solvent.  
   
   
       45 . The method of  claim 42 , wherein the reaction mixture is stirred for a period of about 1 to about 4 hours at a temperature of about 20° C. to about 40° C.  
   
   
       46 . The method of  claim 45 , wherein the period is about 2 hours.  
   
   
       47 . The method of  claim 45 , wherein the temperature is at about room temperature.  
   
   
       48 . The method of  claim 31 , wherein the carbamoyl oxime of formula V is purified and isolated.  
   
   
       49 . The method of  claim 31 , wherein the reduction in step c) is carried out at a temperature of not more than 75° C.  
   
   
       50 . The method of  claim 49 , wherein in step c) about 2 equivalents to about 4 equivalents of acetic acid is added to the reaction mixture per mol of the carbamoyl oxime of formula V.  
   
   
       51 . The method of  claim 49 , wherein in step c) an organic co-solvent is to the reaction mixture.  
   
   
       52 . The method of  claim 51 , wherein the organic co-solvent is toluene.  
   
   
       53 . An isolated enantiomer of a carbamoyl acylamide indan of formula I  
     
       
         
         
             
             
         
       
     
     wherein R is a carbamoyl represented by R 1 R 2 NCOO—, wherein R 1  and R 2  are each independently selected from hydrogen, a straight or branched chain alkyl group or a benzyl group.  
   
   
       54 . The isolated enantiomer of a carbamoyl acylamide indan of  claim 53 , wherein R 1  is methyl.  
   
   
       55 . The isolated enantiomer of a carbamoyl acylamide indan of  claim 53 , wherein R 2  is ethyl.  
   
   
       57 . The isolated enantiomer of a carbamoyl acylamide indan of  claim 53 , wherein R 1  is methyl and R 2  is ethyl.  
   
   
       58 . A method of preparing a carbamoyl amino indan of formula VI  
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are each independently selected from hydrogen, a straight or branched chain alkyl group or a benzyl group, and R 3  is a substituted or unsubstituted, straight or branched C 1 -C 6  alkyl or heteroalkyl from the isolated enantiomer of a carbamoyl acylamide indan of  claim 53 .  
   
   
       59 . The method of  claim 58 , wherein the carbamoyl amino indan of formula VI is Ladostigil.